The human epidermal growth factor receptor ErbB/HER family of receptor tyrosine kinases (RTK) includes four members: EGFR (ErbB1/HER1), HER2 (c-Neu, HER2), HER3 (HER3) and HER4 (HER4). The HER receptors comprise an extracellular glycosylated domain consisting of four structural domains, marked 1 to 4, followed by a transmembrane domain and an intracellular C-terminal part containing a kinase domain for coupling to signalling pathways. Except for HER3, the intracellular region contains a tyrosine kinase activity. Signalling is mediated through ligand-induced receptor dimerization and subsequent phosphorylation that leads to the activation of cytoplasmic signalling pathways. HER2 has no specific ligand because it is naturally under an “active” conformation. The other HER receptors exist as inactive monomers with the molecules folded in such a way to prevent dimerization. Ligand binding to domains 1 and 3 induces major conformational changes ultimately exposing the dimerization loop in domain 2 of the receptor. This exposure of the dimerization loop allows for receptor dimerization.
The HER3 receptor, that has been first described in 1990, is the only HER family member receptor that lacks the intrinsic kinase activity and downstream signalling is achieved through heterodimerization. Thus, the HER3 receptor, as a monomer, is called “non-self” and cannot form homodimers. Binding of the ligand Heregulin (HRG) to HER3 receptor triggers the heterodimerization of HER3 with the others HER family receptors (HER2 preferentially). Within the heterodimer, the HER3 kinase domain acts as an allosteric activator of its HER family partner.
HER3 is implicated in tumorigenesis of various cancers including breast and ovarian cancer (Lee-Hoeflich S T, Cancer Res. 2008; McIntyre E, Breast Cancer Res Treat. 2010; Tanner B, J Clin Oncol. 2006). HER3 expression correlates with tumor progression and reduced patient survival in malignant melanoma and metastases, and is associated with decrease survival in ovary cancer. Importantly, in breast cancer, tumors with low HER2 expression, which are not eligible to Herceptin treatment, often are “programmed” to strongly express HER3 (Smith et al. Br. J. Cancer 2004), and HER2+++ tumors, which become resistant to Herceptin after prolonged treatment, are “re-programmed” to strongly express HER3 (Narayan, Cancer Res. 2009). Cetuximab resistance was also associated with HER3 over-expression in lung cancer (Wheeler, Oncogene 2008) and colorectal carcinomas (Lu Cancer Res 2007), together with dysregulation of EGFR internalization/degradation. Recently, HER3 over-expression was significantly associated with worse metastasis-free survival in colorectal carcinoma (Ho-Pun-Cheung, Int J Cancer 2010). Thus, HER3 over-expression and compensatory signalling through activation of the PI3K/AKT pathway are implicated in the development of resistance to treatment with HER-targeted therapies (antibodies and TKI) (Wheeeler 2008, Lu 2007, Narayan, 2009, Sergina, 2007) but also to treatment with IGFR-targeted therapies (Desbois-Mouthon, Clin Cancer Res 2009) and with chemotherapeutic agents (Kruser, Exp Cell Res 2010).
All these findings suggest that HER3-targeted agents, and in particular antibodies, might help to further understand the role of HER3 signalling in cancers and especially be used as efficient immunotherapeutics.
At present, no therapeutic anti-HER3 antibody is commercialized although the scientific literature strongly emphasizes the interest of targeting HER3 in therapeutic oncology. Two human antibodies are currently under development by Merrimack Pharmaceuticals/Sanofi Aventis (MM-121 antibody; PCT WO2008/100624) and U3 PharmaAG/Daiichi Sankyo/Amgen (U3-1287 or AMG-888; PCT WO2007/077028). MM-121 antibody is involved in a phase I clinical trial in NSCLC and in a phase I/II trial in ER+PR+ HER2− breast cancer. U3-1287 antibody is in phase I in NSCLC in association with Erlotinib. One EGFR/HER3 bispecific antibody DL11f (Genentech; PCT WO2010/108127) is still in research development. One HER2/HER3 bispecific antibody MM-111 (Merrimack Pharmaceuticals; PCT WO2005/117973, WO2006/091209) is involved in phase I/II clinical trials, alone or in combination with trastuzumab or lapatinib, in HER2-amplified breast cancer.
All the above mentioned antibodies block the heregulin-binding site of the HER3 receptor, thus reducing these antibody therapies to ligand-addicted tumors. Targeting HER3 with antibodies that are not directed to the heregulin-binding site of HER3 should make possible to bypass the resistance to targeted therapies or chemotherapy in resistant HER2-amplified breast cancer, to broaden the application field of targeted therapies to HER2low breast cancer, which are currently not eligible for such treatment, or to treat triple-negative breast cancers, which express HER3 and for which no targeted therapy is available yet.